MD4350C1 - Delta crystalline form of the L-arginine salt of perindopril, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Abstract

The present invention relates to the delta crystalline form of the L-arginine salt of perindopril of formula (I): characterized by the following maximum points of powder X-ray diffraction, measured using a copper antibody diffractometer and expressed in Bragg angle values. 2 theta (°): 4.3, 11.0, 11.1, 13.2, 14.6, 16.0 and 21.9, as well as a process for its preparation by crystallization or recrystallization from a binary mixture of acetonitrile, ethyl acetate or methyl-tert-butyl ether and dimethylsulfoxide or a ternary mixture of acetonitrile, dimethylsulfoxide and toluene, at a temperature greater than 20 ° C; and the pharmaceutical compositions containing it. The process described provides the delta crystalline form of the L-arginine salt of perindopril of formula (I) which has increased stability.

Description

The present invention relates to the delta crystalline form of the L-arginine salt of perindopril with formula (I):

to a process for its preparation and to the pharmaceutical compositions that contain it.

Perindopril and its pharmaceutically acceptable salts, especially its arginine salt, possess valuable pharmacological properties. Their main property is to inhibit the enzyme converting angiotensin I (or kininase II), which makes it possible, on the one hand, to prevent the transformation of angiotensin I decapeptide into angiotensin II octapeptide (vasoconstrictor), and, on the other hand, the degradation of bradykinin (vasodilator) in inactive peptide. These two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, especially in hypertension, heart failure and stable coronary artery disease.

Perindopril, its preparation and therapeutic use were described in the European patent [1]. The arginine salt of perindopril (hereafter perindopril-arginine) was first described in the European patent [2]. The alpha and beta crystalline forms of perindopril-arginine have been described in European patents [3] and [4]. The gamma crystalline form of perindopril-arginine was described in the patent application [5]. A process for obtaining perindopril-arginine was described in the patent [6].

Considering the pharmaceutical value of perindopril-arginine, it was very important to obtain this compound with excellent stability. More specifically, the present invention relates to the delta crystalline form of the compound of formula (I) above.

The delta crystalline form of perindopril-arginine, according to the invention, can be characterized by its X-ray diffractogram according to Figure 1 and/or by its NMR spectrum of the solid substance according to Figure 3.

In the absence of excipients and impurities, the delta crystalline form of perindopril-arginine according to the invention can be characterized by the following powder X-ray diffractogram, measured using a diffractometer with a copper anticathode and expressed as the interplanar distance d, the Bragg angle 2- theta and relative intensity (expressed as a percentage in relation to the most intense line):

Angle 2 theta (°) Interplanar distance d [Å] Relative intensity [%] 4.34 20.37 66.2 5.57 15.86 5.2 11.04 8.02 57.5 11.15 7.94 47.5 11.87 7.454 35.0 12.47 7.09 17.9 13.21 6.70 33.6 14.06 6.30 6.6 14.64 6.05 31.8 16.03 5 .53 17.5 17.11 5.18 5.6 18.27 4.85 4.1 19.23 4.61 100 19.44 4.57 17.8 20.04 4.43 13.6 21, 11 4.21 3.7 21.93 4.05 23.0 22.20 4.00 16.9 22.61 3.93 21.2 23.21 3.83 4.5 24.30 3.66 2 .3 25.09 3.55 9.4 25.95 3.43 1.7 29.54 3.02 4.2

Each line is considered to have an accuracy of ± 0.2° in 2-theta. The relative intensities are presented for information purposes. The X-ray diffraction spectrum on the powder was obtained under the following experimental conditions:

diffractometer Panalytical X'Pert Pro,

X'Celerator detector,

copper anticathode, voltage 40kV, current intensity 30mA,

mounting the transmission; fixed sample,

temperature: ambient environment,

measurement range: 3° to 40°,

increase between each measurement: 0.017°,

measurement time at each stage: 49 s,

no internal reference,

experimental data processed with X'Pert Highscore software (Version 2.2a).

In the presence of impurities or excipients, especially in the presence of lactose, certain X-ray diffraction peaks of the perindopril-arginine delta form according to the invention may be obscured.

In the given case, depending on the nature of the excipients or impurities, the delta crystalline form of perindopril-arginine, according to the invention, can be characterized by the following maximum points of X-ray diffraction on the powder, measured using a diffractometer with a copper anticathode and expressed in 2-theta angle value form, (°): 4.3, 11.0, 11.1, 13.2, 14.6, 16.0 and 21.9; or 4.3, 11.0, 11.1, 11.9, 13.2, 14.6, 19.2, 21.9 and 22.6; or 4.3, 11.0, 11.1, 11.9, 12.5, 13.2, 14.6, 16.0, 19.2, 19.4, 21.9, 22.2 and 22 ,6.

The delta crystalline form of the arginine salt of perindopril was also characterized by solid state NMR spectroscopy. The 13C NMR spectrum of the solid substance was recorded at ambient temperature using a Bruker SB Avance spectrometer with a 4 mm CP/MAS SB VTN sensor under the following conditions:

- frequency: 125.76 MHz,

- spectral width: 40 kHz,

- sample rotation frequency under the magic angle: 10 kHz,

- CP (cross-polarization) SPINAL64 decoupling pulse sequence (80 kHz decoupling power),

- repetition delay: 10 s,

- data collection time: 47 ms,

- contact period: 4 ms,

- number of scans: 4096.

A 5 Hz line broadening was applied prior to Fourier transformation. The spectrum obtained in this way was examined against a sample of adamantane (the high frequency peak of adamantane is set at 38.48 ppm (parts per million)). The maximum points recorded were collected in the following table (expressed in ppm ± 0.2 ppm).

No. maximum point Chemical shift (ppm) No. maximum point Chemical shift (ppm) 1 181.2 10 38.4 2 180.5 11 15.6 3 180.1 12 15.2 4 174.0 13 15.0 5 173.7 14 14.5 6 172, 7 7 172.0 8 39.3 9 38.8

The invention also relates to a process for preparing the delta crystalline form of perindopril-arginine by crystallization or recrystallization of perindopril-arginine from a binary mixture of acetonitrile, ethyl acetate or tert-butyl methyl ether and dimethylsulfoxide or from a ternary mixture of acetonitrile, dimethylsulfoxide and toluene, at a temperature higher than 20°C.

In the case of a crystallization process, perindopril-arginine can be obtained starting from another perindopril salt, for example the tert-butylamine salt, which reacts with an acid to obtain perindopril in the free acid form, which is converted into -a salt via arginine in a binary mixture of acetonitrile/ethyl acetate or tert-butyl methyl ether/dimethylsulfoxide or in a ternary mixture of acetonitrile, dimethylsulfoxide and toluene.

In the case of a recrystallization process, the perindopril-arginine used as the starting material can be in anhydrous or hydrated form, in amorphous form or in any crystalline form. If a binary mixture of acetonitrile, ethyl acetate or methyl tert-butyl ether and dimethylsulfoxide is used, the ratio of acetonitrile/dimethylsulfoxide, ethyl acetate/dimethylsulfoxide or methyl tert-butyl ether/dimethylsulfoxide is preferably between 90/10 m/m and 10/90 m/m, the limits being included. The temperature of the medium during crystallization or recrystallization is preferably between 25 and 80°C, inclusive, more preferably between 60 and 80°C, inclusive.

The mixture can advantageously be seeded with a crystallization agent during the cooling step ("seeding" method). If the mixture is not seeded ("no seeding" method), the contact period with the solvent mixture is preferably greater than 6 hours.

The invention also relates to pharmaceutical compositions containing as active substance the crystalline delta form of the compound with formula (I) together with one or more admissible, non-toxic, inert excipients. Among the pharmaceutical compositions according to the invention, the compositions suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration can be mentioned in particular, namely tablets or dragees, sublingual tablets, capsules, glazed tablets, suppositories, creams, ointments, dermal gels, injectable preparations and drinkable suspensions.

The pharmaceutical composition in tablet form is preferably prepared by direct compression.

The effective dose may vary depending on the nature and severity of the disorder, the method of administration, as well as the age and weight of the patient. The effective dose ranges between 1 mg and 20 mg per day in one or more administrations, preferably between 2.5 and 10 mg in a single administration per day.

The pharmaceutical compositions according to the invention may also contain one or more other active substances selected from diuretics such as indapamide, calcium antagonists such as amlodipine and If channel inhibitors such as ivabradine.

If the pharmaceutical compositions according to the invention also contain indapamide, the amount of indapamide is preferably comprised between 0.625 and 2.5 mg, the limits being included. If the pharmaceutical compositions according to the invention also contain amlodipine, the amount of amlodipine is preferably comprised between 5 and 10 mg, the limits being included. If the pharmaceutical compositions according to the invention also contain ivabradine, the amount of ivabradine is preferably comprised between 5 and 30 mg, the limits being included.

The invention is illustrated by the following figures and examples.

Figure 1: Diffractogram of the delta form of perindopril-arginine

Figure 2: Phase diagram of the delta form of perindopril-arginine in a binary acetonitrile/dimethylsulfoxide mixture

Figure 3: Solid state NMR spectrum of perindopril-arginine delta form

In Examples 1 - 4 below, perindopril-arginine, used as the primary material, has a water content of about 3...4%.

Abbreviations:

CPMAS Cross polarization with magic angle rotation

DMSO dimethylsulfoxide

m/m ratio expressed in mass/mass units

NMR Nuclear magnetic resonance

EXAMPLE 1: Delta crystalline form of perindopril-arginine (binary mixture of acetonitrile/dimethylsulfoxide 25/75 m/m, method "without seeding with crystallizing agent")

55.32 g of perindopril-arginine, 297.50 g of dimethylsulfoxide and 94.49 g of acetonitrile are introduced into a reactor. The mixture is heated with stirring at 70°C for 7 hours, then cooled to 40°C at a rate of 1°C/min. After 30 minutes at 40°C, the mixture is filtered through a glass filter. The precipitate on the filter is washed with ethyl acetate and dried overnight at 50°C in a fan oven to obtain the delta crystalline form of perindopril-arginine in 54% yield.

EXAMPLE 2: Delta crystalline form of perindopril-arginine (binary mixture of acetonitrile/dimethylsulfoxide 25/75 m/m, "seeded" method)

52.2 g of perindopril arginine salt, 216 g of dimethylsulfoxide and 76 g of acetonitrile are introduced into a reactor. The mixture is heated, by stirring, to a temperature of 70°C. At 70°C, 0.52 g of perindopril arginine delta form is added to initiate crystallization. The mixture is heated at 70°C for 5 hours (until the turbidity curve stabilizes), then cooled to 40°C at a rate of 0.5°C/min. After 30 minutes at 40°C, the mixture is filtered through a filter medium (diameter = 5 cm, filter threshold = 20 microns) into a 1 L stainless steel cell. The precipitate on the filter is washed with ethyl acetate and dried overnight at 50°C in a fan oven. The delta crystalline form of perindopril-arginine is obtained with a yield of 72% (the crystallization agent being extracted).

EXAMPLE 3: Delta crystalline form of perindopril-arginine (binary mixture of acetonitrile/dimethylsulfoxide 10/90 m/m, "seeded" method)

280 g of perindopril-arginine, 950 g of dimethyl sulfoxide and 97 g of acetonitrile are introduced into a 2 L reactor. The suspension is heated up to a temperature of 80°C when it is observed to pass into solution. The mixture is held at 80°C for 5 minutes, then cooled to 70°C at a rate of 0.5°C/min. Once the temperature of the mixture reaches 70°C, acetonitrile (197 g, pour time = 20 minutes) is added. After addition, the mixture remains clear. The solution is seeded with 6 g of perindopril-arginine delta form. The 70°C stage runs for 45 minutes. The slurry is cooled to 25°C at a rate of 0.5°C/min. It is kept in contact for 4 hours at 25°C until filtration using a 2 L cell. The precipitate on the filter is washed with ethyl acetate and dried overnight at 50°C in a ventilated oven. The delta crystalline form of perindopril-arginine is obtained with a yield of 91% (the crystallization agent being extracted).

EXAMPLE 4: Delta crystalline form of perindopril-arginine (binary mixture of acetonitrile/dimethylsulfoxide 10/90 m/m, "at 25°C" method)

25 g of the arginine salt of perindopril and 90 g of a binary mixture of acetonitrile/dimethylsulfoxide 10/90 (m/m) are introduced into a reactor with mechanical stirring. After a contact period of 72 hours at 25°C with stirring, the transition to the delta form is completed. The reaction mixture is then filtered to isolate the delta crystalline form of perindopril-arginine in 79% yield.

EXAMPLE 5: Delta crystalline form of perindopril-arginine, starting from perindopril (in free acid form), in a binary mixture of acetonitrile/DMSO 25/75

Suspend perindopril (12.5 g, 1 equiv.) and L-arginine (5.32 g, 0.9 equiv.) in a mixture of acetonitrile (20 g, d=0.787) and DMSO (61 g, d= 1,100). The reaction mixture is heated at 50°C overnight. The product is then isolated by filtration through a glass filter. The precipitate on the filter is washed and dried. The delta crystalline form of perindopril-arginine is obtained with a yield of 79% relative to perindopril.

EXAMPLE 6: Perindopril-arginine delta crystalline form (binary mixture of ethyl acetate/dimethylsulfoxide 70/30 m/m, "seeded" method)

15 g of perindopril-arginine and 43.6 g of DMSO are introduced into a 0.5 L reactor. The concentration of perindopril-arginine in the mixture is 25.6% (percentage by mass). The mixture is heated to about 70°C, then 102 g of ethyl acetate is added over 20 minutes (the ratio of ethyl acetate/DMSO is equal to 70/30 m/m). The mixture is seeded at 70°C with 0.3 g of delta crystalline form. After seeding, the mixture is maintained at 70°C with stirring for 2 hours, then cooled to 20°C at a rate of 0.2°C/min, followed by a contact period of 16 hours. Isolation of the product is achieved through a filter medium (porosity 0.41 µm) in a cell. The solid is washed once with a mixture of ethyl acetate/DMSO and twice with ethyl acetate and is dried in a vacuum oven at 50°C. The delta crystalline form of perindopril-arginine is obtained with a yield of 93% (the crystallization agent being extracted).

EXAMPLE 7: Pharmaceutical composition

Formula for preparing 1000 tablets, each containing 5 mg of active substance:

Perindopril delta form arginine 5 g Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g

EXAMPLE 8: Pharmaceutical composition

Tablet containing 10 mg of perindopril arginine, with a final mass of 100 mg:

Perindopril delta form arginine 10 mg Lactose monohydrate 64.2 mg Microcrystalline cellulose 25 mg Magnesium stearate 0.5 mg Silica colloidal anhydrous 0.3 mg

EXAMPLE 9: Thermal stability

The thermal stability of the delta form at 110°C in an open cylinder was compared with

of the shapes from the state of the art. The results are as follows:

Crystalline form Conditions Purity HPLC (%) form α according to EP 1 989 182 t=0 99.8 76 hours at 110°C 98.8 form β according to EP 2 016 051 t=0 99.6 76 hours at 110°C 98 ,3 γ form according to WO 2009/157018 t=0 99.7 76 hours at 110°C 93.4 amorphous form t=0 99.3 76 hours at 110°C 91.0 form obtained according to the SI 23001 process t=0 99.1 76 hours at 110°C 86.9 form δ according to the present invention t=0 99.7 76 hours at 110°C 99.5

These results demonstrate that the delta crystalline form of perindopril-arginine possesses

an improved thermal stability compared to other known forms.

1. EP 049658 A1 1982.04.14

2. EP 1354873 A1 2003.10.22

see page 2

3. EP 1989182 A1 2008.11.12

4. EP 2016051 A2 2009.01.21

5. WO 2009157018 A2 2009.12.30

see Examples 4-13; Claims

6. SI 23001 A 2010.09.30

see Claims 4

Claims (1)

The delta crystalline form of the L-arginine salt of perindopril of formula (I): characterized by the following maximum points of X-ray diffraction on the powder, measured using a diffractometer with a copper anticathode and expressed in values of the Bragg angle 2 theta (°): 4.3, 11.0, 11.1, 13.2, 14.6, 16.0 and 21.9. The delta crystalline form of the compound with formula (I) according to claim 1, characterized by the following maximum points of X-ray diffraction on the powder, measured with a diffractometer with a copper anticathode and expressed in values of the Bragg angle 2 theta(°): 4, 3, 11.0, 11.1, 11.9, 12.5, 13.2, 14.6, 16.0, 19.2, 19.4, 20.0, 21.9, 22.2 and 22.6. The delta crystalline form of the compound of formula (I) according to claim 1, characterized by the following X-ray powder diffraction pattern, measured with a copper anticathode diffractometer and expressed by values of the interplanar distance d, the Bragg angle 2 theta and the intensity relative expressed as a percentage in relation to the most intense line: Angle 2 theta (°) Interplanar distance d (Å) Relative intensity (%) 4.34 20.37 66.2 5.57 15.86 5.2 11.04 8.02 57.5 11.15 7.94 47.5 11.87 7.454 35.0 12.47 7.09 17.9 13.21 6.70 33.6 14.06 6.30 6.6 14.64 6.05 31.8 16.03 5 .53 17.5 17.11 5.18 5.6 18.27 4.85 4.1 19.23 4.61 100 19.44 4.57 17.8 20.04 4.43 13.6 21, 11 4.21 3.7 21.93 4.05 23.0 22.20 4.00 16.9 22.61 3.93 21.2 23.21 3.83 4.5 24.30 3.66 2 .3 25.09 3.55 9.4 25.95 3.43 1.7 29.54 3.02 4.2 The delta crystalline form of the compound of formula (I) according to claim 1, characterized by the 13C CPMAS NMR spectrum of the solid substance having the following maximum points expressed in ppm: No. maximum point Chemical deviation (ppm) No. maximum point Chemical deviation (ppm) 1 181.2 10 38.4 2 180.5 11 15.6 3 180.1 12 15.2 4 174.0 13 15.0 5 173.7 14 14.5 6 172, 7 7 172.0 8 39.3 9 38.8 Process for preparing the delta crystalline form of the compound with formula (I), according to one of claims 1 - 4, by crystallization or recrystallization from a binary mixture of acetonitrile, acetate ethyl or methyl-tert-butyl ether and dimethylsulfoxide or from a ternary mixture of acetonitrile, dimethylsulfoxide and toluene, at a temperature higher than 20°C. Process according to claim 5, in which the binary mixture of acetonitrile, ethyl acetate or methyl-tert-butyl ether and dimethylsulfoxide has a mass ratio of acetonitrile/dimethylsulfoxide, ethyl acetate/dimethylsulfoxide or methyl-tert-butylether/dimethylsulfoxide varying between 90/10 and 10/90. Process according to claim 5 or claim 6, wherein the temperature of the medium is between 25 and 80°C, inclusive. A process according to claim 7, wherein the mixture is heated to a temperature between 60 and 80°C. Process according to one of claims 5 - 8, wherein the mixture is seeded with the delta crystalline form. Pharmaceutical composition containing, as active substance, the compound according to one of claims 1 - 4, in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers. Pharmaceutical composition according to claim 10, characterized in that it also contains a diuretic, a calcium antagonist or an If current inhibitor. Pharmaceutical composition according to claim 11, characterized in that the diuretic is indapamide. Pharmaceutical composition according to claim 11, characterized in that the calcium antagonist is amlodipine. Pharmaceutical composition according to claim 11, characterized in that the If current inhibitor is ivabradine. Compound according to one of claims 1 to 4 for use in the treatment of cardiovascular diseases. A compound according to one of claims 1-4 for use in the treatment of hypertension, heart failure or stable coronary artery disease.